EP0841925A1 - Antagonistes des recepteurs a l'endotheline - Google Patents

Antagonistes des recepteurs a l'endotheline

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Publication number
EP0841925A1
EP0841925A1 EP96928036A EP96928036A EP0841925A1 EP 0841925 A1 EP0841925 A1 EP 0841925A1 EP 96928036 A EP96928036 A EP 96928036A EP 96928036 A EP96928036 A EP 96928036A EP 0841925 A1 EP0841925 A1 EP 0841925A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
methoxy
substituted
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP96928036A
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German (de)
English (en)
Other versions
EP0841925B1 (fr
EP0841925A4 (fr
Inventor
Juan Ignacio Luengo
John Duncan Elliott
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication of EP0841925A4 publication Critical patent/EP0841925A4/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to novel pyrroles, pyrazoles and triazoles, pharmaceutical compositions containing these compounds and their use as endothelin receptor antagonists.
  • Endothelin is a highly potent vasoconstrictor peptide synthesized and released by the vascular endothelium. Endothelin exists as three isoforms, ET- 1 , ET-2 and ET-3. [Unless otherwise stated "endothelin” shall mean any or all of the isoforms of endothelin]. Endothelin has profound effects on the cardiovascular system, and in particular, the coronary, renal and cerebral circulation. Elevated or abnormal release of endothelin is associated with smooth muscle contraction which is involved in the pathogenesis of cardiovascular, cerebrovascular, respiratory and renal pathophysiology. Elevated levels of endothelin have been reported in plasma from patients with essential hypertension, acute myocardial infarction, subarachnoid hemorrhage, atherosclerosis, and patients with uraemia undergoing dialysis.
  • endothelin has pronounced effects on blood pressure and cardiac output.
  • An intravenous bolus injection of ET (0.1 to 3 nmol/ g) in rats causes a transient, dose-related depressor response (lasting 0.5 to 2 minutes) followed by a sustained, dose-dependent rise in arterial blood pressure which can remain elevated for 2 to 3 hours following dosing.
  • Doses above 3 nmol/kg in a rat often prove fatal.
  • Endothelin appears to produce a preferential effect in the renal vascular bed. It produces a marked, long-lasting decrease in renal blood flow, accompanied by a significant decrease in GFR, urine volume, urinary sodium and potassium excretion.
  • Endothelin produces a sustained antinatriuretic effect, despite significant elevations in atrial natriuretic peptide. Endothelin also stimulates plasma renin activity.
  • ET is involved in the regulation of renal function and is involved in a variety of renal disorders including acute renal failure, cyclosporine nephrotoxicity, radio contrast induced renal failure and chronic renal failure.
  • the cerebral vasculature is highly sensitive to both the vasodilator and vasoconstrictor effects of endothelin. Therefore, ET may be an important mediator of cerebral vasospasm, a frequent and often fatal consequence of subarachnoid hemorrhage. ET also exhibits direct central nervous system effects such as severe apnea and ischemic lesions which suggests that ET may contribute to the development of cerebral infarcts and neuronal death.
  • Circ. 83: 701, 1991 heart failure, proliferation of vascular smooth muscle cells,
  • endothelin has been found to be a potent constrictor of isolated mammalian airway tissue including human bronchus (Uchida et al.. Eur J. of
  • Endothelin may play a role in the pathogenesis of interstitial pulmonary fibrosis and associated pulmonary hypertension, Glard et al.. Third International Conference on Endothelin, 1993, p.
  • ARDS Adult Respiratory Distress Syndrome
  • Endothelin has been associated with the induction of hemorrhagic and necrotic damage in the gastric mucosa (Whittle et al.. Br. J. Pharm. 95: 1011-1013,
  • Endothelin stimulates both bone resorption and anabolism and may have a role in the coupling of bone remodeling. Tatrai et al. Endocrinology. Vol. 131, p.
  • endothelin antagonists may be useful as male contraceptives.
  • Endothelin modulates the ovarian/menstrual cycle, Kenegsberg, J. of Clin. Endo. and Met.. Vol. 74, No. 1, p. 12, and may also play a role in the regulation of penile vascular tone in man, Lau et al.. Asia Pacific J. of Pharm.. 1991, 6:287-292 and Tejada et al.. J. Amer. Phvsio. Soc. 1991, H1078-H1085. Endothelin also mediates a potent contraction of human prostatic smooth muscle, Langenstroer et al..
  • endothelin receptor antagonists would offer a unique approach toward the pharmacotherapy of hypertension, acute and chronic renal failure, ischemia induced renal failure, sepsis-endotoxin induced renal failure, prophylaxis and/or treatment of radio-contrast induced renal failure, acute and chronic cyclosporin induced renal failure, cerebrovascular disease, cerebrovascular spasm, subarachnoid hemorrhage, myocardial ischemia, angina, congestive heart failure, acute coronary syndrome, myocardial salvage, unstable angina, asthma, primary pulmonary hypertension, pulmonary hypertension secondary to intrinsic pulmonary disease, atherosclerosis, Raynaud's phenomenon, ulcers, sepsis, migraine, glaucoma, endotoxin shock, endotoxin induced multiple organ failure or disseminated intravascular coagulation, cyclosporin-induced renal failure and as an adjunct in angioplasty for prevention of restenosis, diabetes, diabetic retinopathy,
  • This invention comprises compounds represented by Formula (I) and pharmaceutical compositions containing these compounds, and their use as endothelin receptor antagonists which are useful in the prevention or treatment of a variety of cardiovascular and renal diseases including but not limited to: hypertension, acute and chronic renal failure, cyclosporine induced nephrotoxicity, benign prostatic hypertrophy, pulmonary hypertension, migraine, stroke, subarachnoid hemorrhage, cerebrovascular vasospasm, myocardial ischemia, angina, congestive heart failure, unstable angina, coronary vasospasm and myocardial salvage, the sequelae of diabetes including but not limited to: atherosclerosis, diabetic nephropathy, diabetic retinopathy, retinopathy, diabetic macrovascular disease; and as an adjunct in angioplasty for prevention of restenosis.
  • This invention further constitutes a method for antagonizing endothelin receptors in an animal, including humans, which comprises administering to an animal in need thereof an
  • This invention also constitutes intermediates represented by Formula (II).
  • the present invention provides a process for the preparation of a compound of Formula (I)(d).
  • P is tetrazol-5-yl, CO2R6 or C(O)N(R6)S(O) q R 1 o;
  • R a is independently hydrogen or Chalky!
  • Rj is independently hydrogen, Ar, C ⁇ _ lkyl or C ⁇ _6 alkoxy;
  • R2 is
  • R3 and R5 are independently R13OH, C ⁇ galkoxy, S(O) q R ⁇ 1 , N(R )2 > NO2, Br, F, I, Cl, CF3, NHCOR 6 , R13CO2R7, -X-R9-Y, -X(C(R 6 ) 2 )OR 6 , -(CH 2 )mX'R8 ⁇ r -X(CH2) n R8 wherein each methylene group within -X(CH2) n Rg may be unsubstituted or substituted by one or two -(CH2) n Ar groups; R4 is independently R ⁇ , OH, C1.5a.koxy, S(O) q R ⁇ , N(R6>2. Br, F, I, Cl or NHCOR , wherein the C ⁇ _5alkoxy may be unsubstituted or substituted by OH, methoxy or halogen; ⁇ is independently hydrogen or Cj.galkyl;
  • R7 is independently hydrogen, C ⁇ _ ⁇ oal y_ > C2-iQ ⁇ dkenyl or C2-8alkynyl, all of which may be unsubstituted or substituted by one or more OH, N(R )2» CO2 12, halogen or XCj.ioalkyl; or R7 is (CH2) n Ar; Rg is independently Rj 1 ; CO2 7, CO2C(Rj ⁇ )2 ⁇ (CO)XR7, PO3(R7)2, SO2NR7R11, NR 7 SO R ⁇ 1, CONR 7 SO R ⁇ 1, SO3R7, SO2R7, P(O)(OR 7 )R 7 ,
  • R9 is independently a bond, C ⁇ _ ⁇ oall-enylene, Ci.io lkylidene, C 1.1 ⁇ alkynylene, all of which may be linear or branched, or phenylene, all of which may be unsubstituted or substituted by one of more OH, N(R6)2, COOH or halogen;
  • RlO is independently Cj.ioalkyl, N(R )2 or Ar;
  • Rl 1 is independently hydrogen, Ar, Ci.galkyl, C2-galkenyl, C2-galkynyl, all of which may be substituted or unsubstituted by one or more OH, CH2OH, N(R )2, or halogen;
  • Rl2 is independently hydrogen, C ⁇ lkyl, C2-6alkenyl or C2-7alkynyl;
  • Rj3 is independently divalent Ar, C ⁇ _ ⁇ oalkylene, C ⁇ _ ⁇ oalkylidene,
  • C2-io a lkenylene all of which may be unsubstituted or substituted by one or more OH, CH2OH, N(R ⁇ )2 or halogen;
  • R[4 is independently hydrogen, C ⁇ _ ⁇ oalkyl, XC ⁇ _ ⁇ oalkyl.
  • Ar or XAr R L 5 is independently hydrogen, Ar, C1.galkyl, or XAr;
  • i6 is independently C ⁇ _ lkyl or phenyl substituted by one or more C ⁇ _6_lkyl, OH,
  • B is independently -CH2- or -0-;
  • Zj and Z2 are independently hydrogen, XRg, Ci .galkyl, (CH2) CO2R6»
  • °(CH2)m N aC(O)NR a SO2Ri6 tetrazolyl which may be substituted or unsubstituted by Ci ⁇ alkyl, CF3 or C(O)R6; m is independently 1 to 3; n is independently 0 to 6; q is independently 0, 1 or 2; provided R$ j R4 and R5 are not O-O(CH2) n Ar or O-OR ; or a pharmaceutically acceptable salt thereof.
  • alkyl, alkenyl, alkynyl and alkoxy groups may be straight or branched.
  • Halogen may be Br, Cl, F or I.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active form. All of these compounds and their diastereoisomers are contemplated to be within the scope of the present invention. Preferred compounds are those wherein:
  • P is CO2R6; more preferably P is CO2H.
  • R ⁇ is hydrogen
  • Z[ and Z2 are independently hydrogen, CO2R6. (CH2.nOH, C ⁇ alkyl or
  • R3 and R5 are independently hydrogen, CO2R . OH, C] _galkoxy,
  • Ci-galkyl N(R 6 )2 * NO 2 , Br, F, Cl, I, R 13 CO 2 R7.
  • R3 and R5 preferably do not represent hydrogen.
  • R3 preferably represents Br, Cl, C]_galkoxy e.g. methoxy;
  • X(CH2) n R8- wherein X preferably represents O, n is 0, 1, or 2, and Rg is preferably selected from:
  • R is preferably H; tetrazolyl optionally substituted by Cj.galkyl e.g. ethyl;
  • R7 is H or Ci.galkyl e.g. methyl
  • R ⁇ preferably is Ci.galkyl (e.g. methyl, isopropyl, or t-butyl) or phenyl optionally substituted by Br, Cl, F, Ci.galkyl e.g. methyl
  • Rg is phenyl or pyridyl substituted by one or more Br, Cl, CO2H, CH2OH
  • R5 is Ci.galkoxy e.g. methoxy, or N(R )2 wherein R6 preferably is H or methyl.
  • R4 is hydrogen, OH, C ⁇ _5alkoxy, N(Rg)2, Br, F, Cl, I, NHCOCH3, or S(O) q C ⁇ _ 5alkyl wherein the C ⁇ _5alkyl may be unsubstituted or substituted by OH, methoxy or halogen. R4 is more preferably hydrogen.
  • R is hydrogen or Ci.galkyl e.g. methyl and ethyl.
  • R7 is hydrogen, C ⁇ _ ⁇ oalkyl, C2-io a l ⁇ enyl or C2-galkynyl, all of which may be unsubstituted or substituted by one or more OH, N(R6)2> CO2 12.
  • halogen, or R7 is (CH2)nAr.
  • R7 is (CH2) n Ar, n is preferably zero or 1 and Ar is preferably phenyl substituted or unsubstitued by halogen or C 1.5 alkoxy.
  • Rj 1 is hydrogen, phenyl, pyridyl wherein the phenyl and pyridyl may be substituted or unsubstituted by one or two Cj ⁇ alkyl groups; Ci.galkyl, C2-8alkenyl, C2-galkynyl, all of which may be substituted or unsubstituted by one or more OH, CH2OH, N(R6)2. or halogen;
  • Rl2 is hydrogen or Cj ⁇ alkyl.
  • Rl3 is phenyl, pyridyl, or C2-io a H c yl ene * all of which may be unsubstituted or substituted by one or more CO2R . OH, CH2OH, N(R )2> or halogen;
  • Rl5 is preferably hydrogen or Ci ⁇ alkyl e.g. ethyl, isopropyl, n-butyl, cyclopropylmethyl or cyclopropylethyl.
  • R15 is Chalky! in suitable solvents such as methanol and water in the presence of sodium acetate provides a pyrazole of Formula (6).
  • Aldehyde condensation may be effected by heating in the presence of pyridine and acetic acid. Conversion of an ester of formula (9) into an acid may be carried out using conventional deprotection techniques i.e. hydrolysis.
  • Ri Ci-8 alkyl and n is 1, may be prepared starting from 4-methoxyphenol (10)
  • substituents R15 R3, R4 and R5 and be introduced at any appropriate stage of the synthesis, preferably at an early stage, using methods well known in the art.
  • one or more of the substitutents R ⁇ R3, R4 and R5 may therefore represent a precursor for the eventual substituent.
  • a precursor for any of the substituents R ⁇ R3, R4 and R5 means a group which may be derivatised or converted into the desired group R ⁇ R3, R4 and R5. It will be further appreciated that it may be necessary or desirable to protect certain of these substituents (or their precursors) at various stages in the reaction sequence. Suitable precursors and protecting groups as well known to those skilled in the art, as are methods for their conversion of removal respectively.
  • the invention provides for an intermediate of the formula
  • one B is CH2 and the other is O; can be prepared starting by commercially available ketones of Formula (17)
  • Cj. alkyl and M is Li or MgCl; to provide a compound of Formula (24), wherein R a is Ci-6alkyl.
  • a compound of Formula (31 ) may be prepared by reaction of a corresponding organometallic derivative (eg lithium or Grignard) with a trialkyl borate followed by hydrolysis.
  • a compound of Formula (32) may be prepared starting from dimethyl malonate with p-acetaminobenzenesulfonyl azide in a solvent such as acetonitrile in the presence of a base such as triethyl amine to provide dimethyl diazomalonate (34).
  • a diketone of Formula of (38) can be prepared by reacting of a,b-unsatuated ketone of Formula (40)
  • Compounds of Formula (I) and their pharmaceutically acceptable salts may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parenterally, sub-lingually, transdermally, rectally, via inhalation or via buccal administration.
  • Compounds of Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavouring or colouring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used.
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil.
  • a parenterally acceptable oil for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluorome thane .
  • a typical suppository formulation comprises a compound of Formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues.
  • a binding and or lubricating agent for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues.
  • Typical transdermal formulations comprise a conventional aqueous or non- aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • a conventional aqueous or non- aqueous vehicle for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to themselves a single dose.
  • Each dosage unit for oral administration contains suitably from 0.1 mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.1 mg to 100 mg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • Each dosage unit for intranasal administration contains suitably 1-400 mg and preferably 10 to 200 mg per person.
  • a topical formulation contains suitably 0.01 to 1.0% of a compound of Formula (I).
  • the daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • the daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, of a compound of the Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • the daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 500 mg/person.
  • the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity.
  • CHO cell membrane preparation A) CHO cell membrane preparation. CHO cells stably transfected with human ET_ and ETg receptors were grown in 245 mm x 245 mm tissue culture plates in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum. The confluent cells were washed with Dulbecco's phosphate-buffered saline containing a protease inhibitor cocktail (5 mM EDTA, 0.5 mM PMSF, 5 ug/ml of leupeptin and 0.1 U/ml of aprotinin) and scraped in the same buffer.
  • a protease inhibitor cocktail 5 mM EDTA, 0.5 mM PMSF, 5 ug/ml of leupeptin and 0.1 U/ml of aprotinin
  • the cells were lysed by freezing in liquid nitrogen and thawing on ice followed by homogenization (30 times using a glass dounce homogenizer) in lysis buffer containing 20 mM Tris HCI, pH 7.5, and the protease inhibitor cocktail.
  • lysis buffer containing 20 mM Tris HCI, pH 7.5, and the protease inhibitor cocktail.
  • the supernatants were centrifuged at 40,000 x g for 15 min and the pellet was resuspended in 50 mM Tris HCI, pH 7.5, and 10 mM MgCl2 and stored in small aliquots at -70°C after freezing in liquid N .
  • the incubations (30°C, 60 min) were stopped by dilution with cold buffer (20 mM Tris HCI, pH 7.6, and 10 mM MgCl2) and filtering through Whatman GF/C filters (Clifton, NJ) presoaked in 0.1% BSA.
  • the filters were washed 3 times (5 ml each time) with the same buffer by using a Brandel cell harvester and were counted by using a gamma counter at 75% efficiency.
  • EXAMPLE 16 (E)-3-[ 1 - n-Butyl-5-[2-N-ethyl-5-tetrazolyl)methoxy]-4-methoxyphenyl- 1 H-pyrazol- 4-yl]-2-[(5-methoxy-2,3-dihydrofuran-6-yl)methyl]-prop-2-enoic acid
  • EXAMPLE 17 (E)-3-[l-n-Butyl-5-[l-N-ethyl-5-tetrazolyl)methoxy]-4-methoxyphenyl-lH-pyrazol- 4-yl]-2-[(5-methoxy-2,3-dihydrofuran-6-yl)methyl]-prop-2-enoic acid
  • Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
  • a compound of Formula I (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
  • Ta lets/In redi nts Per Tablet
  • Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender.
  • Step 2 Add sufficient water portion-wise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules.
  • Step 3 The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.
  • Step 4 The wet granules are then dried in an oven at 140°F (60°C) until dry.
  • Step 5 The dry granules are lubricated with ingredient No. 5.
  • Step 6 The lubricated granules are compressed on a suitable tablet press.
  • a pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of formula I in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then steriled by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

Nouveaux pyrroles, pyrazoles et triazoles, compositions pharmaceutiques contenant ces composés et leur utilisation comme antagonistes des récepteurs à l'endothéline.
EP96928036A 1995-08-02 1996-08-02 Antagonistes des recepteurs a l'endotheline Expired - Lifetime EP0841925B1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US179295P 1995-08-02 1995-08-02
US1792 1995-08-02
US1098296P 1996-02-01 1996-02-01
US10982 1996-02-01
PCT/US1996/012581 WO1997004772A1 (fr) 1995-08-02 1996-08-02 Antagonistes des recepteurs a l'endotheline

Publications (3)

Publication Number Publication Date
EP0841925A1 true EP0841925A1 (fr) 1998-05-20
EP0841925A4 EP0841925A4 (fr) 2001-10-17
EP0841925B1 EP0841925B1 (fr) 2006-10-04

Family

ID=26669471

Family Applications (2)

Application Number Title Priority Date Filing Date
EP96926243A Expired - Lifetime EP0843551B1 (fr) 1995-08-02 1996-08-02 Antagonistes du recepteur de l'endotheline
EP96928036A Expired - Lifetime EP0841925B1 (fr) 1995-08-02 1996-08-02 Antagonistes des recepteurs a l'endotheline

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EP96926243A Expired - Lifetime EP0843551B1 (fr) 1995-08-02 1996-08-02 Antagonistes du recepteur de l'endotheline

Country Status (25)

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US (5) US5969151A (fr)
EP (2) EP0843551B1 (fr)
JP (2) JPH11511133A (fr)
KR (1) KR19990036032A (fr)
CN (1) CN1196680A (fr)
AP (1) AP9801182A0 (fr)
AT (1) ATE341324T1 (fr)
AU (2) AU717172B2 (fr)
BG (1) BG102229A (fr)
BR (1) BR9609914A (fr)
CA (2) CA2228296A1 (fr)
CZ (1) CZ30498A3 (fr)
DE (2) DE69619116T2 (fr)
EA (1) EA000952B1 (fr)
ES (2) ES2171697T3 (fr)
HU (1) HU220776B1 (fr)
MX (1) MX9800975A (fr)
NO (1) NO980422L (fr)
NZ (1) NZ315846A (fr)
OA (1) OA10755A (fr)
PL (1) PL184272B1 (fr)
RO (1) RO115802B1 (fr)
SK (1) SK282584B6 (fr)
TR (1) TR199800152T1 (fr)
WO (2) WO1997004773A1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR017426A1 (es) 1997-12-08 2001-09-05 Smithkline Beecham Corp Sal de monoargininilo del acido (e)-3-[1-n-butil-5-[2-(2-carboxifenil)metoxi-4-clorofenil]-1h-pirazol-4-il]-2-[(5-metoxi-2,3-dihidrobenzofuran-6-il)metil]-prop-2-enoico, composicion farmaceutica que la contiene, su uso para la manufactura de un medicamento y procedimiento para su preparacion
DE10155076A1 (de) * 2001-11-09 2003-05-22 Merck Patent Gmbh Verwendung von Endothelin-Rezeptor-Antagonisten zur Behandlung von Tumorerkrankungen
JP2006501179A (ja) * 2002-06-27 2006-01-12 ニトロメッド インコーポレーティッド シクロオキシゲナーゼ−２選択的阻害剤、組成物、および使用方法
WO2006075955A1 (fr) * 2005-01-13 2006-07-20 Astrazeneca Ab Derives de pyrazolyl acylsulfonamide utilises en tant qu'inhibiteurs de l'enzyme de conversion de l'endotheline et particulierement utiles dans le traitement d'une maladie pulmonaire obstructive chronique
US7521435B2 (en) * 2005-02-18 2009-04-21 Pharma Diagnostics, N.V. Silicon containing compounds having selective COX-2 inhibitory activity and methods of making and using the same
US8012038B1 (en) 2008-12-11 2011-09-06 Taylor Made Golf Company, Inc. Golf club head
US10086240B1 (en) 2015-08-14 2018-10-02 Taylor Made Golf Company, Inc. Golf club head
US10626096B2 (en) 2015-11-24 2020-04-21 Sanford Burnham Prebys Medical Discovery Institute Azole derivatives as apelin receptor agonist
US10773135B1 (en) 2019-08-28 2020-09-15 Taylor Made Golf Company, Inc. Golf club head

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0403158A2 (fr) * 1989-06-14 1990-12-19 Smithkline Beecham Corporation Acides imidazolyl-alcénoiques
WO1992010189A1 (fr) * 1990-12-14 1992-06-25 Smithkline Beecham Corporation Acides imidazolyl-alcenoiques
WO1996007653A1 (fr) * 1994-09-02 1996-03-14 Smithkline Beecham Corporation Antagonistes du recepteur de l'endotheline

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DE1937241A1 (de) * 1968-08-02 1970-02-19 Sumitomo Chemical Co 3,5-Dioxopyrazolidinderivate und Verfahren zu ihrer Herstellung
JPH01211582A (ja) * 1988-02-16 1989-08-24 Tanabe Seiyaku Co Ltd ベンゾジオキソール誘導体
FR2682379B1 (fr) * 1991-10-09 1994-02-11 Rhone Poulenc Agrochimie Nouveaux phenylpyrazoles fongicides.
WO1994022830A1 (fr) * 1993-03-31 1994-10-13 Smithkline Beecham Corporation Composes chimiques
ATE199151T1 (de) * 1993-08-18 2001-02-15 Banyu Pharma Co Ltd Kondensierte heteroaromatische cyclopentenderivate mit endothelin- antagonistischer aktivität
IL111613A0 (en) * 1993-11-12 1995-01-24 Rhone Poulenc Rorer Ltd Substituted phenyl compounds, their preparation and pharmaceutical compositions containing them

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0403158A2 (fr) * 1989-06-14 1990-12-19 Smithkline Beecham Corporation Acides imidazolyl-alcénoiques
WO1992010189A1 (fr) * 1990-12-14 1992-06-25 Smithkline Beecham Corporation Acides imidazolyl-alcenoiques
WO1996007653A1 (fr) * 1994-09-02 1996-03-14 Smithkline Beecham Corporation Antagonistes du recepteur de l'endotheline

Non-Patent Citations (1)

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Title
See also references of WO9704772A1 *

Also Published As

Publication number Publication date
AU6764596A (en) 1997-02-26
AU717172B2 (en) 2000-03-16
ES2273350T3 (es) 2007-05-01
WO1997004773A1 (fr) 1997-02-13
EP0843551A4 (fr) 1998-08-12
NO980422D0 (no) 1998-01-30
DE69619116T2 (de) 2002-09-19
US5958968A (en) 1999-09-28
TR199800152T1 (xx) 1998-05-21
EP0843551B1 (fr) 2002-02-06
BG102229A (en) 1998-09-30
WO1997004772A1 (fr) 1997-02-13
DE69619116D1 (de) 2002-03-21
DE69636597T2 (de) 2007-08-16
EP0841925B1 (fr) 2006-10-04
CN1196680A (zh) 1998-10-21
KR19990036032A (ko) 1999-05-25
ES2171697T3 (es) 2002-09-16
SK282584B6 (sk) 2002-10-08
AU6646396A (en) 1997-02-26
PL184272B1 (pl) 2002-09-30
HUP9902817A3 (en) 2001-03-28
BR9609914A (pt) 1999-07-06
US6353116B1 (en) 2002-03-05
PL324745A1 (en) 1998-06-08
AP9801182A0 (en) 1998-01-31
CA2228296A1 (fr) 1997-02-13
EP0843551A1 (fr) 1998-05-27
CA2228293A1 (fr) 1997-02-13
HUP9902817A2 (hu) 1999-12-28
DE69636597D1 (de) 2006-11-16
US6096897A (en) 2000-08-01
NO980422L (no) 1998-03-24
NZ315846A (en) 1999-01-28
EP0841925A4 (fr) 2001-10-17
US20020072614A1 (en) 2002-06-13
EA199800185A1 (ru) 1998-10-29
EA000952B1 (ru) 2000-08-28
US6482956B2 (en) 2002-11-19
OA10755A (en) 2002-12-13
SK11398A3 (en) 1998-07-08
US5969151A (en) 1999-10-19
MX9800975A (es) 1998-04-30
RO115802B1 (ro) 2000-06-30
JPH11511133A (ja) 1999-09-28
ATE341324T1 (de) 2006-10-15
CZ30498A3 (cs) 1998-07-15
HU220776B1 (hu) 2002-05-28
JP2001517195A (ja) 2001-10-02

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